The present invention relates to a method for the prevention and/or treatment of vascular disorders and secondary disorders associated therewith, such as depression. The invention is also concerned with a preparation that can be used in the prevention and/or treatment of the aforementioned disorders.
The vascular system in the human body is well described in the art. An important part of the system are the blood vessels, that generally are divided in arteries and veins, dependent whether they transport blood to or from the heart. They vary in size from large (e.g. the aorta) to very small (capillaries). From an anatomical point of view larger blood vessels in general comprise as observed from the lumen side:    1. the tunica intima, that consists of a smooth (mono)layer of endothelial cells and a subendothelial layer that consists of a loose layer of connective tissue,    2. the tunica media, which consists of a layer of (innervated) smooth muscle cells and elastic fibers, and    3. the tunica adventitia which is composed of loosely woven collagen fibers, which are infiltrated by tiny lymphatic and blood vessels.
The endothelial cells in the tunica intima are in direct contact with blood and have a barrier function for the underlying tissue. This barrier function includes selective transport of components from blood to the underlying tissue and vice versa, and protection of the underlying tissue. Endothelial cells get easily damaged due to a wide variety of causes like mechanic forces or interaction with stressor components such as classic anaphylatoxins, and components that may occur in the blood, such as homocysteine or components that result from treatment with certain types of drugs (e.g. chemotherapeutics). Vascular permeability can further be increased by a wide variety of humoral- and cell-derived mediators.
Endothelial dysfunction can result in a wide range of disorders. Damage to the endothelial layer can disturb the physiological functions thereof such as transport properties and expose the underlying tissue to stressors. Monocytes may migrate to these damaged spots, get caught by adhesion molecules, differentiate into macrophages, which, when activated, may start up an inflammatory reaction. Due to this reaction cytokines may be released, which may trigger the release of reactive oxygen species, or change coagulation behaviour of blood components. This may result in occurrence of plaques in the arteries, which may ultimately result in hypertension, atherosclerosis and (later) arteriosclerosis.
Atherosclerosis may lead to an impaired blood supply to tissue, which may then become ischaemic. This may lead to damage to cells and even apoptosis of the cells that depend on the oxygen and nutrient supply via these blood vessels. Tissue that has become ischaemic may thus lose functional capacity.
There is increasing evidence that depression, and in particular late-life depression, are caused by or associated with vascular disorders. Cerebral white matter lesions are presently thought to represent vascular abnormalities. White matter lesions have been related to affective disorders and a history of late-onset depression in psychiatric patients. Their relation with mood disturbances in the general population is not clearly understood. For the majority of persons with a depression syndrome the age of onset is in the late twenties, but it is also common to have an onset after age forty. Between 1 and 2% of elderly persons suffer from major depression. A different aetiology is suggested for the depression in late life. It has been suggested that a cerebro-vascular component is probably more important in the aetiology of late-life depression than genetic of psychological factors. Various associations between depression and stroke or hypertension have been found the last 5 years. Lowering hypertension may reduce depression in older depressed people suffering from hypertension/atherosclerosis.
The following articles report on correlations observed between vascular disorders and depression:    Rao R., “Cerebrovascular disease and late life depression: an age old association revisited”, Int J Geriatr Psychiatry. (2000) May; 15(5):419–33. Review.    de Groot J C, de Leeuw F E, Oudkerk M, Hofman A, Jolles J, Breteler M M, “Cerebral white matter lesions and depressive symptoms in elderly adults”, Arch Gen Psychiatry (2000) November; 57(11):1071–6    Krishnan K R, Doraiswamy P M, Clary C M, “Clinical and treatment response characteristics of late-life depression associated with vascular disease: a pooled analysis of two multicenter trials with sertraline”. Prog Neuropsychopharmacol Biol Psychiatry. (2001) February; 25(2):347–61.    Lloyd A J, Grace J B, Jaros E, Perry R H, Fairbairn A F, Swann A G, O'Brien J T, McKeith, Depression in late life, cognitive decline and white matter pathology in two clinico-pathologically investigated cases”, Int J Geriatr Psychiatry. (2001) March; 16(3):281–7
Depression and related disorders, sometimes referred to as “mood disorders”, can severely impair functioning in normal life of people suffering therefrom, leading to decreased happiness for the persons suffering therefrom but also influencing the people in their surroundings. In the worst cases these disorders can lead to violence or suicide.
Depression and related disorders can be distinguished by short periods of depression or fluctuating heavy moods and longer periods of more severe mood disorders. The latter periods can be caused by psychosis or disturbance of the personality causing extreme behaviour. Examples are bipolar or unipolar depression, schizophrenia and ADHD.
Other causes of depression can be extremely stressful external factors such as loss of a relative, which can disturb the mental balance. Also hormonal changes such as occur during menstruation or menopause can cause longer or shorter periods of emotional distress.
Further it has been noted that certain groups in society, such as elderly, suffer more from depression. This could be related to other causes, beside those mentioned above, including certain changes in the brain of these groups of people. In addition it has been found that depression is frequently encountered in individuals who suffer from neurological disorders, such as dementia and Parkinson's disease.
Beside psychological therapy, which is not effective for every type of patient and chemical drugs, which can be addictive and have severe side effects, no treatment is available.
For the prevention and treatment of vascular disorders no suitable therapy is available either. Vascular disorders and the consequences thereof are a major cause of death in the Western countries. At present vascular disorders are treated by prescribing specific diets that are restricted in cholesterol, saturated fatty acids and in some cases sodium content and by administering drugs that are designed to lower blood pressure (e.g. diuretics), and plasma levels of cholesterol e.g. statins (or oilier compounds that are able to inhibit the activity of HMG-CoA reductase).
Though some of the treatments are indeed effective in treating part of the phenomena associated with vascular problems, the treatments are not 100% effective in solving the real problem (the cause) and they may demonstrate undesired systemic side effects.